The present invention relates to a device and method for stimulating salivation, and more particularly, to an implantable device and a method of using same for stimulating salivation by the application of electrical energy to nerves in the region of the oral cavity to produce salivation by reflex action, by creating parasympathetic outflow to the salivary glands, parotid, submandibular or sublingual.
The following background information is derived, in part, from A. D. Korczyn, Ed. "Handbook of autonomic nervous system dysfunction" Marcel Dekker, N.Y., 1995, pp. 293-309.
Salivary glands have been recognized since the 19.sup.th century as typical effector organs of the autonomic nervous system. The classic experiments of Pavlov are a good example of the interest that salivary glands have stirred up among scientists. They illustrate the decisive control the autonomic nervous system exerts on salivary gland. Therefore, salivary glands are sensitive markers of autonomic nervous system function and, as such, may present a variety of disorders related to autonomic nervous system dysfunction.
Applied Anatomy of the Salivary Glands: Human beings possess three pairs of major salivary glands--parotid, submandibular, and sublingual--and a myriad of minor salivary glands spread throughout the oral mucosa. All salivary glands share a common parenchymal structure of acinar units and ducts. The former are composed of acinar cells encircled by myoepithelial cells and circumscribing the acinar lumen. The acinar lumen drains into the ductal system, which reaches the oral cavity. The salivary gland stroma is made up of neurovascular structures and scarce connective tissue.
The salivary gland morphology will be described succinctly here. The parotid glands, the largest of the salivary glands, lie underneath the skin of the cheeks. They secrete their saliva via Stensen's ducts, which open into the oral cavity opposite the upper second molars. Parotid glands have predominantly serous acini, and therefore the fluid they secrete is "watery" and not viscous, as is the fluid secreted by mucous glands.
Innervation of the parotid glands is provided by parasympathetic and sympathetic fibers. The preganglionic parasympathetic fibers of the parotid glands arise from the inferior salivary nucleus in the medulla, from where they travel through the glossopharyngeal nerve, the tympanic nerve and plexus, and the lesser petrosal nerve into the otic ganglion. Here they synapse with fibers in the auriculotemporal nerve, reaching the parotid gland. The sympathetic innervation originates in the superior cervical ganglion, and contacts the parotid gland via the plexus of the external carotid.
The submandibular glands are the second largest salivary glands. These glands and the sublingual glands are situated at the floor of the mouth. These glands empty their secretions into the oral cavity through ducts whose foramina are located sublingually. While submandibular glands have a mixed structure of serous and mucous secretory units, sublingual glands are mainly mucous.
The innervation of submandibular and sublingual glands is similar. Preganglionic parasympathetic innervation originates from the superior salivary nucleus in the pons, reaching the submandibular ganglion after passing along the nervus intermedius (facial nerve) and the chorda tympani. The sympathetic innervation arises from the superior cervical ganglion and reaches the glands by way of the facial artery plexus.
Secretion of Saliva: The greatest part of saliva is secreted by the parotid and submandibular glands. Other contributions to saliva include sublingual and minor gland secretions, gingival exudate, desquamated epithelial cells, blood cells, microorganisms, and their products.
Saliva performs a crucial role in the oral cavity. The full accomplishment of salivary functions depends on proper salivary flow rate and composition. Taste perception is facilitated by saliva carrying food particles onto the taste buds in an appropriate dilution. Salivary amylase and lipase start the digestion of starch and fat. Saliva is also important in the formation of the food bolus and the salivary lubricatory glycoproteins permanently coat oral surfaces, assisting in food mobility and reducing friction between the different oral structures (teeth, tongue, cheeks, lips) and between the structures and foreign elements (food, dental prostheses).
Salivary lubrication, repair, lavage, antimicrobial, and buffering properties contribute significantly to the maintenance of oral hard and soft tissue integrity.
The secretion of saliva is regulated by the autonomic nervous system, with a minor role played by hormones and autocoids. Salivary secretion fluctuates between minimal and maximal rates. The basal secretion of saliva, which is due to the spontaneous activity of the salivary nuclei, displays a circadian rhythm of high amplitude.
The stimuli that enhance salivation are related to eating: tasting, smelling or seeing food, and chewing. These peripheral stimuli are transmitted to the central nervous system, exciting efferent salivary fibers. During meals saliva production rises 5-50 fold over basal secretion.
The accumulated knowledge on salivary gland physiology, which is mostly based on studies performed on animals, explains the role of the autonomic nervous system in saliva secretion. The two autonomic divisions act synergistically to produce salivation by the salivary glands, although sublingual and labial salivary glands lack sympathetic control.
In the parotid and submandibular glands the parasympathetic system is mostly responsible for the water and electrolyte secretion, whereas the sympathetic system mainly regulates the protein (e.g., amylase) secretion.
Autonomic Effects on Acinar Secretory Cells: Postganglionic sympathetic fibers release norepinephrine, which activates alpha- and beta-adrenergic receptors on salivary glands. The parasympathetic fibers release acetylcholine, vasoactive intestinal peptide (VIP), and substance P. Beta-adrenergic and muscarinic cholinergic receptors are present at a much higher density on parotid membranes than other receptors.
The signal transduction mechanisms differ among the salivary gland receptors. Beta-adrenergic and VIP receptors activate adenylate cyclase that catalyzes cAMP formation from ATP. Conversely, alpha-2-adrenergic receptor activation blocks cAMP generation and inhibits salivary secretion. Muscarinic cholinergic, alpha-1-adrenergic, and substance P receptors activate phospholipase C, and, as a result, diacylglycerol (DAG) and inositol triphosphate (ITP) are formed from the hydrolysis of phosphatidylinositol-4,5-biphosphate.
Each second messenger created by the transduction mechanisms mobilizes its own pathway. Signaling of cAMP leads primarily to exocrine protein secretion. DAG likewise induces protein excretion, but to a much lower extent. The pathway of ITP involves calcium mobilization, which causes fluid secretion through the activation of ion channels. Unlike the pancreas and the kidney, fluid production by salivary gland does not depend upon perfusion pressure but on the creation of osmotic pressure by active ion transport across the acinar cells into the lumen. This osmotic pressure drags water from the interstitium into the acinar lumen to produce an isotonic fluid, termed promary saliva.
Autonomic Effects on other Salivary Gland Components: Myoepithelial cell contraction, which contributes significantly to saliva secretion, is induced by parasympathetic and sympathetic stimulation, acting upon muscarinic cholinergic and alpha-adrenergic receptors, respectively.
Primary saliva fluid, secreted from acinar cells, is modified in the ductal system to produce a hypotonic fluid, which is secreted into the oral cavity. Sodium and chloride are reabsorbed into ductal epithelial cells, which, in turn, release potassium and bicarbonate ions. A short contact time of primary saliva with ductal cells, which occurs when salivary flow increases upon salivary gland stimulation, diminishes electrolyte interchange. The ductal electrolyte transport is under autonomic control, but, in addition, it is influenced also by hormonal and metabolic factors.
Contraction of glandular blood vessels is the only sympathetic inhibitory effect of salivary gland function. This particular activity takes place independently of other sympathetic regulatory influences on the salivary gland. Parasympathetic-induced vasodilatation is mediated by both cholinergic and VIP receptors. When vasodilatation is needed in order to supply water for saliva production, parasympathetic influences largely overpower sympathetic vasoconstrictive effects.
Dysfunction of Salivary Glands: Autonomic nervous system abnormalities are mostly manifested by salivary gland hypofunction (SGH). Sialorrhea (excessive drooling) and hypersalivation are controversial terms that have been traditionally described in a number of conditions such as cerebral palsy, Parkinson's disease and seasickness. However, the scientific literature on salivary gland function in these disorders has shown either a normal or decreased salivary output or lacks adequate quantitative salivary measurements.
Xerostomia (sensation of dry mouth) may be due to a variety of factors, although SGH is its most frequent cause. SGH generates xerostomia when salivary flow does not suffice to compensate for loss of fluid from the mouth. Oral fluid is consumed by swallowing, absorption by the oral mucosa, and evaporation from the mouth. Xerostomia is thought to become a significant symptom when the unstimulated flow is reduced by 50% or more.
Xerostomia is a common symptom and may affect between one-fifth and one-third of the adult population. It affects women more commonly than men. When caused by SGH, xerostomia may be accompanied by a variety of oral hard and soft tissue changes. The lower the salivary flow rate, the less salivary defense and lubrication components enter the oral cavity. The mucosal tissues may become painful, "burning", ulcerated, or atrophic. An increased rate of dental caries with a distinctive cervical pattern of decay, which is extremely difficult to treat, is typically seen. Xerostomic denture wearers exhibit a high prevalence of oral candidiasis.
Decreased salivary secretion may lead to functional oral disturbances as well. Chewing, swallowing, and speaking are difficult and taste sensation may be diminished. These disorders compromise not only the biological integrity of the individual but also the general quality of life and well-being.
SGH can be linked primarily to autonomic nervous system dysfunction or to salivary gland parenchyma changes. The most prominent of the former is caused by the use of pharmacological agents, while Sjogren's syndrome is the most common condition leading to significant salivary gland structural alterations.
Causes of xerostomia in cases of normal salivary gland function include body dehydration, oral mucosal sensory alterations, psychological disturbances and habits, such as smoking, mouth breathing and alcohol consumption. Causes of xerostomia in cases of salivary gland hypofunction primarily associated with autonomic nervous system disorders include intake of drugs acting on the autonomic nervous system, and poisoning, Alzheimer's disease, depression, diabetes, Fabry's disease, salivary gland denervation and pure dysautonomias. Causes of xerostomia in cases of salivary gland hypofunction primarily associated with salivary gland parenchymal alterations include Sjogren's syndrome, head and neck radiotherapy, bone marrow transplantation, chronic hepatitis C, HIV infection, sarcoidosis, amyloidosis and hyperlipoproteinemia.
The question of whether age, per se, is a causative factor of SGH has not been completely determined. The reports in the literature on the impact of aging on salivary flow are conflicting. The clinician should be cautious in considering advanced age, per se, as the reason for complaints of xerostomia among aging patients. Intake of drugs or coextistent disease, so common in old age, are co-founding that could also explain these symptoms.
SGH Induced by Drugs and Poisoning: The use of medication is the most common cause of SGH. A high percentage of dental patients aged 65 and above (73%) were found to take prescription drugs routinely. A majority of them (87%) take multiple medications. Approximately half of the institutionalized geriatric population has been reported to receive one or more drugs with a hyposalivatory side effect.
A list of over 400 drugs that cause xerostemia as an adverse side effect has been published (Sreebny L M and Schwartz S S. A reference guide to drugs and dry mouth. 2.sup.nd edition, Gerodonotology 1997; 14:33-47, which is incorporated by reference as if fully set forth herein). Salivary flow is particularly reduced when two or more hyposalivatory drugs are taken simultaneously. The use of medications with xerostomic effects has been found to be a good predictor of root caries in the elderly.
Drugs can affect autonomic nervous system function at several sites: central nervous system (CNS) centers: preganglionic, ganglionic, postganglionic, and effector site neurotransmission; and effector cells. The classes of pharmacological agents causing xerostomia include (i) agents affecting primarily the autonomic nervous system; (ii) agents with anticholinergic side effects; and (iii) agents causing xerostomia by other or unknown mechanisms. Agents affecting primarily the autonomic nervous system include peripheral alpha adrenergic blocking agents, e.g., prazosin, doxazosin, terazosin and alfuzosin; beta-blocking agents, e.g., propranolol, atenolol, esmolol, metoprolol and oxprenolol; antimuscarinic agents, e.g., atropine, scopolamine, propantheline, pirenzepine and trihexyphenidyl; central alpha-2 agonists, e.g., clonidine and methlydopa; neuron-blocking agents, e.g., bretylium and monoamine oxidase inhibitors; and ganglion-blocking agents, e.g., mecamylamine. Agents with anticholinergic side effects include dopamine receptor-blocking agents, e.g., phenothiazines (i.e., fluphenazine, thioproperazine, levomepromazine and thioridazine) and thioxanthenes; tricyclic antidepressants, e.g., amitriptyline, clomipramine, desipramine, doxepin and imipramine; benzodiazepines, e.g., clonazepam, clorazepate and diazepam; H1 antihistamines; Lithium salts; and other drugs, such as, disopyramide and anorexiants. Agents causing xerostomia by other or unknown mechanisms include calcium channel blockers, e.g., verapamil (alpha-blocking activity); diuretics; narcotic analgesics; steroids; nonsteroidal anti-inflammatory drugs; angiotansin converting enzyme inhibitors and serotonin specific receptor inhibitors.
Most of the literature on this issue is based on patients' subjective complains and basic research. Reports on quantitative salivary flow data obtained through well-controlled clinical studies on subjects receiving medication are scarce.
Dry mouth is a clinical manifestation of botulism and poisoning with atropine and scopolamine. Botulinum toxins interfere with acetylcholine release from cholinergic nerve endings. Atropine produces muscarinic receptor blockage.
Salivary Gland Disorders Induced by Diseases:
Alzheimer's Disease: It has been reported that submandibular gland function is compromised, (while parotid function is unaltered), among nonmedicated patients with Alzheimer'S disease, possibly due to dehydration and structural abnormalities of the pons.
Depression: Stress-related dry mouth is the result of central inhibition on the salivary centers. Whole and parotid salivary flow rates have been found to be reduced among depressed patients, particularly in involutional and manic-depressive cases. However, since most depressed individuals are taking medication, it is now difficult to perform salivary studies on these patients.
Diabetes: Thirst is a frequent complaint of diabetic patients. However, the literature is controversial as to the relationship among thirst, xerostomia, and SGH among diabetic patients. In one study, parotid function has been found to be reduced in diabetic patients with peripheral neuropathy, but normal in other patients with diabetes. These results are consistent with parasympathetic denervation of the parotid gland in diabetic autonomic neuropathy. However, in other studies diabetic autonomic neuropathy was associated with either no change in whole salivary flow rate or even an increase in parotid gland output.
Fabry's Disease: Fabry's disease is a metabolic disorder accompanied by sympathetic and parasympathetic involvement. Reduced saliva production is one of the autonomic manifestations of this disease.
Salivary Gland Denervation: After division of autonomic fibers, neurotransmitters are released in greater amounts until stores become depleted. This induces a degenerative secretion, lasting a few days. The acinar cells gradually develop supersensitivity to neurotransmitter stimulation. At later stages after parotid denervation, a paradoxical phenomenon has been described: copious salivation following atropine administration, similar to the paradoxical effect of atropine on the denervated pupil.
Pure Dysautonomias: Cholinergic dysfunction leading to SGH has been described in Shy-Drager syndrome, postganglionic cholinergic dysautonomia, and panautonomic dysfunction. Familial dysautonomia, also known as Riley-Day syndrome, is an autosomal recessive disease occurring almost exclusively in Jewish children of Askenazi origin. This disease is characterized by progressive impairment of sensory and autonomic functions. One of the many signs reported in this disorder is drooling, either due to "denervation supersensitivity" of the partially denervated salivary gland, resulting in hypersalivation, or impaired deglutition.
Sialadenosis: Sialadenosis is a symmetrical, painless, noninflammatory, recurrent parotid swelling, associated with a variety of metabolic alterations, such as diabetes mellitus, liver diseases, malnutrition and the use of antihypertensive agents. The swelling of the parotid glands is the manifestation of acinar cell enlargement in response to increased sympathetic activity. In fact, considerably higher beta-receptor concentration in salivary gland were found in sialadenosis. Adequate evidence of the presence of alterations in salivary secretion rate is lacking.
Bell's Palsy: The differential assessment of bilateral submandibular gland function as part of chorda tympani function appears to be valuable in the prediction of Bell's Palsy prognosis. This assessment can be carried out by means of submandibular duct cannulation or scintigraphy. If the affected side exhibits reduction of at least 75% compared to the normal side, there is usually no recovery. An increased salivary concentration of Na.sup.+ has been found in patients with facial paralysis, possibly due to alterations in the ductal Na.sup.+ pump.
Treatment of Autonomic Nervous System-Associated Salivary Gland Dysfunction: It is crucial to instruct patients with dry mouth on the importance of maintaining oral health. A well-designed preventive program should include meticulous oral hygiene procedures and the routine use of fluoride supplements.
Modification of Drug Regimen: Patients often continue to take medications even after the original cause that has led to their prescription has been eliminated. In such cases, it might be possible to suspend or reduce the intake of the offending drugs. When this is not possible, splitting of the daily dose into smaller, more frequently taken doses may alleviate the xerostomic effects. Drug scheduling may be modified to achieve peak blood levels that do not coincide with periods during the day when maximal oral dryness is reported by the patient. In other cases, substitution of drugs with equipotent agents with fewer side effects may be attempted. Yet, in many cases no substitute is available, and xerostomia persists.
Salivary Gland Chemical Stimulation: Chemical stimulation of salivary glands, may have good symptomatic benefit on patients with dry mouth, providing the oral cavity with its natural saliva. The flow of saliva through the salivary gland ducts also helps to prevent ascending infections of the salivary glands. However, only patients with responsive salivary gland tissue may benefit from this approach. Usually chewing gums formulated with noncariogenic sweeteners and flavors are better accepted by patients with dry mouth than are mouthwashes acting as salivary stimulants and substitutes. The salivary gland-stimulating effect of citric acid is short acting and, therefore, frequently not satisfactory to achieve symptomatic improvement of xerostomia. The effectiveness of citric acid is also limited by its irritating effects on the oral mucosa. Patients should be cautioned about the demineralizing effect on the teeth of frequent use of citric acid rinses.
Saliva Substitutes: Treatment of SGH base on artificial saliva is largely palliative. It attempts, by the use of a variety of oral rinses, to provide lubrication of the oral soft tissues and to limit damage to the hard tissues. However, treatment of the sensation of dryness and soft tissue changes with saliva substitutes is often unsuccessful.
Carboxymethycellulose (CMC) and animal mucins are used to replace the salivary effects (lubrication, viscosity) on oral functions, such as food emulsion and swallowing. However, a study has shown that one-third of patients with dry mouth have found CMC-based oral rinses inadequate to treat their condition.
Other components of artificial salivas are sweeteners (xylitol or sorbitol) and electrolytes. The addition of electrolytes is aimed at mimicking natural saliva composition and at providing the potential for remineralization.
Systemic/Local Sialogogues: Pilocarpine produces its cholinomimetic effects chiefly by a direct action on the autonomic effector cells, although ganglionic stimulation may participate in the production of its total pattern of response. Administration of 5 mg pilocarpine HCl has been shown to increase the output of parotid and submandibular secretions and to relieve xerostomia for up to 3 hours.
A major drawback of pilocarpine is its potential for inducing adverse cholinergic effects on patients with cardiovascular alterations, asthma, or active duodenal ulcers. However, no alterations in basic cardiovascular parameters were observed in patients with dry mouth who have received 15-20 mg pilocarpine daily. Mild side effects, such as sweating, flushing, and urinary urgency were occasionally observed.
The muscarinic cholinergic stimulating agent bethanecol chloride and the cholinesterase inhibitor pyridostigmine have been used to treat xerostomia induced by a variety of factors. Subjective improvement of xerostomia as a result of anetholetrithione intake has been reported. It is believed that the mechanism of action of anetholetrithione on salivary glands is linked to proliferation of muscarinic receptors on the acinar cell membranes. Since a major part of the drug is metabolized in the liver, its use is contraindicated in patients with significant hepatic diseases.
It has recently been reported that yohimbine induces a significant increase in saliva secretion in healthy subjects and in depressed patients treated with tricyclic antidepressants. Yohimbine enhances norepinephrine release from nerve terminals by preferential blockade of presynaptic alpha-2 receptors: it acts possibly also in chorda tympani nerve endings leading to enhanced acetylcholine release and submandibular saliva secretion. However, high doses of the drug may produce significant autonomic effects, such as increases in systolic blood pressure and anxiety. Another drawback of yohimbine may be the highly variable bioavailability of the drug in humans.
The mucolytic agent bromhexine has been used to treat xerostomia in patients with Sjogren's syndrome, but no conclusive evidence on the utility of this agent is available.
Slow-releasing devices to be attached to or placed around teeth or implanted into the gum are disclosed, for example, in U.S. Pat. Nos. 3,624,909; 3,688,406; 4,020,558; 4,175,326; 4,681,544, 4,685,883, 4,837,030; 4,919,939; 5,614,223 and 5,686,094. These devices serve for releasing various medicaments within the oral cavity of a patient. The latter two patents disclose devices for controlably releasing drugs for the treatment of xerostomia.
Electric Stimulation: U.S. Pat. Nos. 4,519,400 and 4,637,405 teach a stimulator for inducing salivation by neural stimulation. The stimulator includes a housing which may be received in the oral cavity of a user, the housing enclosing electronic signal generating means and electrodes for applying a signal to neurally sensitive locations of the oral cavity to induce salivation. In its method aspect, the invention involves stimulation of salivation by the application of an electrical signal to neurally sensitive locations.
This device has numerous limitations. In one embodiment thereof, it is held in the mouth cavity of a user for a time period and then it is removed therefrom, to be reinserted into the mouth cavity at a later time. In another version, it is held in place by being connected to a tooth of the upper jaw. This configuration is limiting because it causes great discomfort to the user and affects the user's ability to speak, eat and/or drink.
There is thus a widely recognized need for, and it would be highly advantageous to have, an implantable device and a method of using same for stimulating salivation, devoid of the above limitations.